Acne Vulgaris is a common skin disorder that affects 80% of the population, typically teenagers and young adults. Over 50 million people in the US are affected by acne generating a $2 billion market for acne treatments, 80% of which is derived from prescription medications. Although acne is not a life-threatening condition, it still has a high psychosocial impact resulting in depression, anxiety, anger, suicidal thoughts, physical scarring and decreased quality of life. The primary causes of acne are the overproduction of sebum by sebaceous glands, hyperkeratinization of follicular epithelium, P. acnes proliferation and inflammation. Unfortunately, the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics. Retinoids have been used for more than 20 years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne. However, because of serious concerns regarding the teratogenic properties of retinoids, their use is now part of an FDA-mandated registry program. In addition, isotretinoin has been linked to serious side effects including clinical depression, inflammatory bowel disease and sensitive skin. There is a clear need for safe and efficacious treatments that target sebum production in sebocytes. In Phase I studies we screened a novel class of compounds identified in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis. We successfully identified active molecules, developed initial structure activity relationship around a lead scaffold and demonstrated in vivo efficacy that is comparable to isotretinoin in an animal model of sebogenesis. In this Phase II application we will use a medicinal chemistry approach to expand this series of compounds using our sebocyte screening platform and in vivo models to identify multiple novel orally bioavailable small molecules for lead optimization. Using this approach, our goal is to deliver safe, effective sebum inhibitors for the treatment of acne vulgaris.